Intercostal nerve cryoablation therapy for the repair of pectus excavatum: a systematic review

Introduction The minimally invasive repair of pectus excavatum (PE) is a painful procedure that can result in long-term hospitalization and opioid use. To mitigate the length of stay and opioid consumption, many different analgesia strategies have been implemented. The aim of this study is to review the use and patient outcomes of intercostal nerve cryoablation (INC) during PE repair reported in the literature. Methods An unfunded literature search using PubMed identifying articles discussing INC during PE repair from 1946 to 1 July 2023 was performed. Articles were included if they discussed patient outcomes with INC use during PE repair. Articles were excluded if they were reviews/meta-analyses, editorials, or not available in English. Each article was reviewed for bias by analyzing the study methods, data analysis, patient selection, and patient follow-up. Articles comparing outcomes of INC were considered significant if p-value was <0.05. Results A total of 34 articles were included in this review that described INC use during pectus repair. Most supported a decreased hospital length of stay and opioid use with INC. Overall, INC was associated with fewer short-term and long-term complications. However, the researchers reported varied results of total hospital costs with the use of INC. Conclusion The review was limited by a paucity of prospective studies and low number of patients who received INC. Despite this, the present data support INC as a safe and effective analgesic strategy during the repair of PE.


Introduction
Pectus excavatum (PE) is the most common chest wall deformity characterized as an inward depression of the sternum, affecting one in every 250 adults with a female predominance of 5:3 (1)(2)(3).The sternal depression is hypothesized to be secondary to inward overgrowth of the costal cartilage, which is commonly exacerbated during puberty (4,5).PE may have a myriad of adverse effects, ranging from impaired cardiopulmonary performance during rest and exercise to poor psychosocial outcomes (2).
The current gold standard for the repair of PE is the minimally invasive repair of PE (MIRPE), or the Nuss procedure, which has smaller incisions and decreased operative time and blood loss when compared with an open chest wall reconstruction, or the Ravitch procedure.MIRPE is a very safe procedure when performed in combination with a sternal elevation and intrathoracic visualization but is associated with more pain than the Ravitch procedure (6)(7)(8).In an attempt to mitigate patients pain following MIRPE, many analgesic strategies have been proposed including the use of thoracic epidurals (TEs), intravenous patient-controlled analgesia (PCA), indwelling chest wall catheter infusion or elastomeric pain pumps (EPPs), and local or regional nerve blocks (9)(10)(11)(12)(13).
The use of intercostal nerve cryoablation (INC) as an analgesic adjunct during the MIRPE was first reported in 2016 by Keller et al. (14) when they found that the use of INC was associated with a decreased length of stay (LOS) and inpatient opioid consumption when compared with TE.INC is thought to have temporary neurosensory effects and takes advantage of the ability of the peripheral nerves to regenerate following injury (15)(16)(17).Since the introduction of INC during the MIPRE, many surgeons have adopted this technique.The aim of our study is to review the reported patient outcomes of those who had undergone INC during PE repair in the current literature.

Methods
A literature search was performed using "Cryoablation" or "Cryotherapy" and "Pectus Excavatum" using PubMed from 1946 to 1 July 2023.All titles and abstracts were reviewed for content and subject relevance.Articles were excluded from the review if they did not pertain to patient outcomes of PE repair with the use of INC, if the article was not available in English, if the article was a review or meta-analysis, or if the article was an opinion piece.In addition, the citations were reviewed for all included articles.If a cited article was identified that pertained to INC during PE repair, it was then included in the review.
Two reviewers screened all the articles for the inclusion and exclusion criteria; upon selection, each article was reviewed, and data were abstracted pertaining to the study methods, patient demographics, INC technique, operative duration, INC comparison group, patient LOS, inpatient and outpatient oral morphine equivalence (OME), patient-reported pain scores, hospital charges, and surgical complications.The details pertaining to INC were recorded including number of nerves and intercostal spaces cryoablated and the duration and temperature of nerve cryoablation.The operative duration was recorded as both surgical time and operating room time if reported.The patient-reported pain scores were recorded on a Likert scale from 1 to 10.All complications reported by the authors were abstracted.The data points were excluded in this review if they were not reported by the authors or if any data points were unclear.
An in-depth assessment of articles discussing the primary outcome of LOS and secondary outcomes among patients who had undergone INC vs. a control analgesic strategy was conducted.Both prospective and retrospective studies were included in this review.Comparisons of outcomes were abstracted between study groups; outcomes between groups were considered statistically significant if a p-value of <0.05 was reported.All comparisons of LOS, opioid usage, and pain scores were compiled in a table regardless of statistical significance.The patient demographics were reviewed between those who received INC and those who received a different analgesic strategy to ensure patient similarities between groups.To reduce bias, the authors of this manuscript independently reviewed each study that was identified using PubMed for the inclusion criteria.

Results
A total of 44 articles were identified via the defined literature search (33) and article citation review (5); of these articles, 34 were included in our review.Of the 10 excluded articles, four did not pertain to INC outcomes following the MIRPE (18-21), three were opinion editorials (22)(23)(24), two were review articles (25,26), and two were not in the English language (27).Of the articles included, the majority were single-center retrospective reviews (29/34), with one randomized control trial and four prospective reviews.A total of 47% of the articles included both pediatric and adult patients in their analysis; however, the majority of the patients were pediatric, ≤18 years old, with an average age of less than 21 years in all articles.Most articles contained fewer than 60 patients who had undergone INC, and the largest study contained 350 patients.A majority (24/34) compared patient-related outcomes between INC and a control group.The control groups included multimodal pain regimen, thoracic epidural PCA, paravertebral nerve block with and without continuous infusion, elastomeric pain pump, or unspecified analgesia strategy (Table 1).
INC was reported to be performed via an intrathoracic approach under thoracoscopic visualization in 90% of the cases.The number of intercostal nerves that were cryoablated ranged from eight to 12 between the intercostal space of T3-T8.Velayos et al. (39) reported performing INC preoperatively via a percutaneous approach.Almost all the researchers applied the cryoprobe for a single 2 min duration to each intercostal nerve, with one article reporting a single 1 min application of the cryoprobe.The temperature of the applied cryoprobe reached temperatures ranging from <−40 to −70°C.The operative times during the MIRPE with INC ranged from 60 to 153 min (Table 1).

Primary outcomes
The primary outcome discussed in the majority of the articles was hospital LOS and opioid usage (Table 2).The use of INC was associated with a significant decrease in LOS when compared with other analgesic strategies in 21 out of 22 articles (13, 14, 28-30, 32-38, 41-43, 46, 48-52, 54, 55).When comparing LOS between patients who had undergone INC vs. TE placement, Keller et al. (14) found that hospital LOS decreased from 5.8 days to 3.4 days.Other researchers have corroborated INCs effect on hospital LOS when compared with TE placement reporting a decreased LOS of 2-3.5 days (13,28,30,33,34,41,46,48,50,52,54).One study found no significant change in LOS when comparing INC with EPP (29); however, this study was possibly underpowered to find a statistical difference among cohorts, with only six patients receiving INC as part of their care.Alternatively, INC was found to reduce hospital LOS when compared with EPP in every other study that compared these  (13, 14, 28, 30, 31, 35, 37, 38, 41-43, 46, 48-51, 53, 54).A majority of these studies reported opioid use in terms of OME milligrams and reported the total hospital OME milligram; however, most did not account for the LOS in the non-INC cohort when reporting opioid use (14, 28, 29, 31, 35, 38, 40-43, 48, 50, 51, 54).All researchers that compared opioid OME by individual hospital days reported a significant lower amount of opioid consumption among the INC cohort than those with other analgesic strategy (37,46,48,49,53).Of all articles comparing opioid consumption between an INC and non-INC cohort, all found equivocal or lower opioid consumption among those who had INC during MIRPE.The researchers found a significant decrease in the total OME prescription at discharge and duration of opioid use post-MIRPE when INC was utilized (28,35,37,38,43,51,54).
The effect of INC on visual analog pain scores (VAPS) varied between investigators, with less than half (5/11) of the articles finding a significant decrease in VAPS when INC was used (Table 2) (13, 28-30, 33, 41, 44, 46, 48, 49, 53).INC was associated with significantly lower VAPS only during the initial postoperative hospitalization.At the outpatient follow-up, there was no differences found in VAPS; however, VAPS were generally low following discharge in both the INC and non-INC cohorts.

Complications
The complications associated with INC were reported in 50% of the articles reviewed.The overall complication rate was either significantly lower or no difference was found between the INC and non-INC cohorts (28,31,35,38,40,43,45,50,51,53,54,59).Postoperative urinary retention was found to improve with INC with rates ranging 4%-8% compared with the 14%-34% in those who did not have INC (38,43).Keller et al. 2016 and Sun et al. 2021 reported higher rates of clinically significant pectus bar migration requiring reoperation in patients with INC.In these studies, bar migration occurred in 8%-12% of patients who had INC; however, neither study provided a statistical comparison of bar migration between the INC group and a control.The bar migration was hypothesized to be secondary to an increased activity in patients with INC due to an improved pain control (14,38).However, an increased bar migration has not been supported by other studies (28,31,59).In fact, the largest cohort study of INC in MIRPE, containing 350 patients, reported bar migration occurring in less than 1% of patients who received INC (59).
Neurosensory outcomes following the use of INC were reported in 16% of studies (13,32,37,40,51).A complete chest wall sensory return following cryoablation was reported to occur in 76.9%-100% of patients 1 year post-INC.No difference in neuropathic pain was found between patients with INC and those with an alternative analgesic strategy (13,51).Zobel et al. conducted a retrospective review comparing neuropathic pain between adolescent and adult patients using a validated neuropathic pain survey.They found that neuropathic pain was more common in adults (>21 years of age) (32).In children, the incidence rate of neuropathic pain was 0% at 12 months (40).While these studies demonstrate a relatively low risk for developing persistent sensory loss or chronic neuropathic pain, most studies were retrospective in nature, creating an inherent bias in their findings.No articles discussed in detail how chest wall sensory examinations were performed or validated.In addition, only one article compared sensory outcomes between  (13).This finding suggests that some sensory loss may be attributable to surgical technique; however, this study was underpowered to truly compare sensory loss and recovery between INC and MIRPE.

Economic impact
The majority of articles that discuss total hospital costs and charges found that INC is associated with a decrease in cost when compared with other analgesic strategies (35,37,50,51,54).The median overall cost of MIRPE with INC ranged from $14,072 to $33,848 compared with $18,335-$40,813 MIRPE without INC.All investigators who included an itemized cost analysis found that the use of INC was associated with a greater operative room cost (35,50,54).One of five studies found that the use of INC was associated with higher hospital cost.Perez

Discussion
Since the introduction of INC during MIRPE, it has consistently shown to decrease hospital LOS and opioid usage among children and adolescents.In addition, INC has a favorable side effect profile with minimal associated morbidity.INC is routinely performed on the bilateral chest wall under direct visualization, using a single lung ventilatory strategy, between the intercostal nerves T3 and T8 at a temperature of −40°C to −60°C for a 2-min duration (Figure 1).The cryoprobe is allowed to actively rewarm to a temperature of −4°C prior to removal from the chest wall to avoid tissue fracture/injury.Care is taken to avoid inadvertent contact of the cryoprobe and lung tissue to avoid thermal pulmonary injury and delayed pneumothorax; in addition, the anesthesiologist continues contralateral single lung ventilation for 3 min from the last INC to avoid thermal injury from the chest wall.
The largest series of patients undergoing the MIRPE with INC was reported in 2022 (53).This study was a retrospective review that captured 350 patients who had undergone INC between December 2017 and August 2021.The mean age of the study  (23).Future prospective studies are warranted to compare the long-term neurosensory effects of INC and to determine the incidence rate of chronic neuropathic pain.
In addition to neurosensory outcomes, there is a paucity of literature regarding the effect of INC on the psychosocial and physiologic quality of life of the patient.The repair of PE has been shown to have a significant improvement in both self-perception and physiologic status of the patient (60-62).In the current literature, only one article addressed pulmonary functions following MIRPE with INC.Lai et al. (53) demonstrated that INC did not worsen the pulmonary function of the patient, as measured by incentive spirometry, when compared with the use of an elastomeric pain pump.Research is needed to address the effects that INC has on the psychosocial and cardiopulmonary performance outcomes following MIRPE.Furthermore, an investigation of the impact that INC has on postoperative patient activity is warranted as some have reported unacceptably high rates of pectus bar migration following INC use (14,38).
In the current literature that reviews the use of INC during the repair of PE, most studies were performed retrospectively leading to inherent bias and limitations (63).Of the studies that were conducted in a prospective manner, all were possibly underpowered without discussion of a power calculation and the largest number of patients receiving INC in any study being 35 (13,33,48,49,57,58).Among the prospective studies, INC was only compared against TE, PCA, and intercostal nerve blocks.In addition, there has only been one randomized control trial comparing INC with any other analgesic strategy.Again, this study was limited by a small sample of five patients, who had undergone INC as part of the MIRPE (13).The paucity of appropriately powered prospective studies ultimately limits the conclusions that can be drawn with regard to the true effect that the INC has on patient outcomes.Future prospective randomized control trials are needed to compare INC with other analgesic strategies.

Conclusion
INC is an effective analgesic strategy following the MIPRE, with its use known to decrease hospital LOS and opioid consumption with minimal morbidity.
Holguin et al. conducted a retrospective review comparing hospital cost between TE use from 2002 to 2020 and INC use from 2017 to 2020.They found an overall increased hospital cost from $21,621 to $24,742 when INC was used compared with TE; the largest contributor to cost with INC was the intraoperative charge of $6,198 vs. $3,916 for TE.However, in their cost analysis, they failed to account for inflation and operative technique, i.e., number of pectus bars implanted, bar stabilization between groups (50).Similarly, Aiken et al. performed a cost analysis of INC compared with a standardized pain control cohort between 2016 and 2019.The total hospital costs were adjusted to 2018 dollars to standardize monetary value across each study year.They found that the total hospital cost was lower in the INC cohort, $21,924, compared with the non-INC cohort, $23,694 (Table 2) (37).

TABLE 1
Application of intercostal nerve cryoablation reported in the literature.
(49,37,40,48,49,rategies57), 38,48,53).EPP only provides analgesia while in place whereas INC provides a prolonged analgesic effect; in the prior studies, EPPs were typically in place for 48-72 h postoperatively and were discontinued prior to discharge.When INC is used in combination with a multimodal pain regimen, the researchers found that patients were able to be routinely discharged on post operative day (POD) 1(33,37,40,48,49, 51, 56,57).Recent publications have demonstrated the feasibility of a same-day discharge when INC is combined with a peripheral nerve block (PNB) with 65%-66% of patients being discharged on POD 0(49, 55, 58).

TABLE 1 Continued
Rettig et al. (54) performed INC during an open repair of PE. a

TABLE 2
Hospital length of stay, opioid use, and pain scores of intercostal nerve cryoablation.

TABLE 2 Continued
this study lacked a control arm that had not undergone INC as part of their pain strategy.Those who do not support the use of INC during MIRPE in children and adolescents argue that while INC has been shown to decrease hospital LOS and opioid consumption, it lacks data supporting long-term safety and efficacy.They further cite that no studies have adequately compared INC with the erector spinae block, which is associated with a short hospital LOS and low opioid use and may spare adolescent patients from the possible neurosensory and neuropathic pain complications of INC MM, multimodal pain regimen; EEP, elastomeric pain pump; PVB, paravertebral block; INB, intercostal nerve block; PACU, post anesthesia care unit.*A statistically significant difference between groups, p < 0.05.